HIV-1 Env remains an attractive target for preventive antiviral therapies as it is the only viral protein exposed on the surface of entering HIV-1 virions. Env consists of a trimer of solvent-exposed glycan-covered gp120 domains, each with a transmembrane gp41 stalk. Gp120 contains the receptor and coreceptor binding sites; gp41 comprises the membrane fusion machinery. The conformation of HIV-1 Env is metastable. Binding to CD4 induces conformational changes in gp120, which unmask the coreceptor (CCR5 or CXCR4) binding site. Coreceptor binding activates gp41, which promotes fusion of the viral and cell membranes.
The limited success in targeting HIV-1 Env can be attributed in part to our incomplete understanding of the structural dynamics of the unliganded HIV-1 Env trimer, a lack of understanding of the molecular mechanism of Env activation, and the high sequence variability of Env. Crystallographic studies have concentrated on the monomeric core of gp120 in the absence of gp41, variable loops, and glycans. The HIV-1 gp120 core exists as an ensemble of different conformers in dynamic equilibrium and requires ligands such as receptor CD4, or chemical crosslinking to adopt a single conformation that permits crystallization. It remains unclear to what extent these structures can be extrapolated to the behavior of the Env trimer. While recent electron tomography studies have provided insights into the structure of trimeric Env on the native virus, the resolution remains low (White et al. (2010) PLoS Pathog 6, e1001249; Liu et al (2008) Nature 455, 109-113; Hu et al. (2011) J Virol 85, 2741-2750). Moreover, no dynamic data exist on the sampling of various conformations, their relative stabilities, or the kinetics of the transitions between states. Thus, despite the existence of a wealth of structural information, the HIV-1 Env trimer and the structural dynamics remain poorly understood.
Understanding the conformational trajectories of HIV-1 Env activation by receptor and coreceptor represents a critical prerequisite for the rational design of antiviral therapies that prevent virus fusion. This is particularly important for inhibitors that target the CD4 binding site. While they can function as competitive inhibitors, they may also act as CD4 mimetics to activate HIV-1 Env and promote infection of cells lacking CD4 (Madani et al (2008) Structure 16, 1689-1701; Schön et al (2006) Biochemistry 45, 10973-10980; Haim et al. (2009) PLoS Pathog 5, e1000360). In contrast, allosteric inhibitors can divert Env to conformations that no longer support virus fusion. Consequently, understanding the conformational trajectories underlying activation or inhibition is of critical importance for the development of antiviral therapies.